Oxazolidinones represent a novel chemical class of synthetic antimicrobial agents. Following a chequered historical development since about the early-1980s, a watershed event took place with the clinical development and release for medical use in the late 2000s of the first representative, Linezolid, of this class1,2 This advance enabled the profiling of the unique properties of the members of this class, which is that they display activity against important Gram-positive human and veterinary pathogens including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin resistant enterococci (VRE) and β-lactam resistant Streptococcus pneumoniae (PRSP). The oxazolidinones also show activity against Gram-negative aerobic bacteria and Gram-positive and Gram-negative anaerobes3.
The deficiencies of this class of oxazolidinones have also surfaced. They are inactive against Enterobacteriaceae4. They are generally bacteriostatic and do not display activity at a useful level against aerobic fastidious Gram-negative pathogens, as well as Gram-negative anaerobes. Moreover their potency for atypical respiratory pathogens such as Mycoplasma pneumoniae, M. hominis, Ureaplasma urealyticium and Chlamydia species is of a borderline range which could result into unacceptable clinical efficacy for the treatment of respiratory tract infections3.
Other limitations that have appeared through the clinical development studies and use of Linezolid and its potential successors in development are that the class has a propensity to induce myelosuppression with consequent thrombocytopenia5. Inhibition of monoamine oxidase by oxazolidinones has prompted a recommendation made to clinicians that clinical use of members of this class be done with caution during concomitant usage of adrenergic or serotonergic agents and selective serotonin reuptake inhibitors6.
Linezolid is shown to have two targets in cells for its inhibitory effects. It binds to the 50S subunit within domain V of the 23S or RNA peptidyl transferase center near the interface with the 30S subunit, thereby blocking the formation of the tMet-tRNA-ribosome-mRNA ternary complex. In addition, linezolid associates with the nascent 50S particle and stops the assembly process7.
Considering that the oxazolidinones are bacteriostatic, as indeed are most other agents that inhibit bacterial protein synthesis, there is a strong likelihood that resistance can emerge under selective pressure during therapy, specially for infections which require a bactericidal therapy to be used. The significant concern related to this class of antibacterials is attributed to this essentially bacteriostatic effect against their prime target pathogens such as staphylococci, enterococci and pneumococci. It is pertinent to quote from the Adis R&D Insight report (Document 013296 dated Dec. 27, 2001) that an oxazolidinone AZD 2563 under clinical development is described to be “ineffective against linezolid-resistant S. pneumoniae”. This concern is further aggravated due to the recent reports of emergence of Linezolid-resistant strains of enterococci and staphylococci in clinics. In fact the first clinical isolates of E. faecium, E. faecalis and S. aureus resistant to linezolid have recently been described8. Also, resistant strains have been generated by serial passage techniques, the resistance being associated with specific mutations in the 23S rRNA gene9.
Our own studies have also led to the identification of novel Linezolid-resistant strains, an embodiment of this invention. It has been reported that in-vitro staphylococci and enterococci resistant to linezolid can be selected only with difficulty8, which through genome characterization studies have shown the resistance to be associated with specific mutations in the 23S rRNA nucleotide sequence. The linezolid-resistant strain of S. pneumoniae ATCC 6303 LR has guanine replacing adenine at the nucleotide position 2160 of 23S rRNA. Similarly, our Linezolid-resistant strains of S. aureus Smith & MRSA 032 have uracil replacing guanine at nucleotide position 2447. These three resistant mutants, harbouring changes in the molecular targets of linezolid, showed significant elevation of MIC values for Linezolid indicating the loss in affinity of the drug to its ribosomal targets.
“Fine tuning” of this class of agents to improve the affinity of its members for the ribosome at existing or altered single or multiple target sites is conceivable, resulting thereby in significantly increasing their potency, and in incorporating bactericidal activity against Linezolid-sensitive/-resistant strains.
The present invention describes a novel series of oxazolidinones which display increased potency, and incorporate bactericidal activity, in contrast to the earlier-described bacteriostatic activity, against Linezolid-sensitive/-resistant strains, thus indicating a differential binding at the conventional site/s of the ribonucleoprotein and/or targeting multiple such receptor sites. In addition, using comparative molecular field analysis10, a study of literature-described oxazolidinones and the novel compounds of the present invention has enabled the identification of newer/additional structural motifs of the oxazolidinone class, novel and non-obvious from the prior art, which support the activity against the Linezolid-sensitive/-resistant pathogens. There is no prior description of oxazolidinones displaying such bactericidal activity or useful activity against Linezolid-sensitive/-resistant or other oxazolidinone-resistant microbial pathogens.
The following publications may be referred to with respect to the statements made in the above-described background information.
1Slee AM, et al., Antimicrob. Agents Chemother (1987) 31:1791-1797;
22nd European Congress of Chemotherapy and 7th Biennial Conference on Antiinfective Agents and Chemotherapy (Final Program), (1998): 93;
3Diekema D J et al., Lancet 2001; 358: 1975-82;
4Zhanel GG et al., Canadian Journal of Infectious Diseases, 2001, 12: 379-390;
5Kuter D J et al., Pharmacotherapy, 2001: 21: 1010-1030;
6Ament P W et al., Am Fam Physician 2002, 65: 663-70;
7Shinabarger D, Exp. Opin. Invest. Drugs (1999) 8:1195-1202; Champrey W S et al., Curr. Microb. 2002, 44: 350-356;
8Zurenko GE et al, In 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington DC, (1999) abstr. 848; Gonzales RD et al., Lancet 2001; 357:1179; Tsiodras S, et al., Lancet 2001; 358: 207-08;
9Swaney SM et al., In 38th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington DC, (1998) abstr. C-104;
10Pae, A. N. et al, Bioorg. & Med. Chem. Lett., 1999, 9:2685-90.
After filing of our pending provisional U.S. application No. 60/395,164 methylenepiperidinyl and methylenepyrrolidinyl oxazolidinone antibacterial agents were described in Kim H Y et al., Bioorg. & Med. Chem. Lett., (2003), 13:2227-2230.